According to the Centers for Disease Control (CDC), vaginitis is an extremely common diagnosis among women of reproductive age, resulting in more than 10 million medical office visits every year. The vast majority of cases of vaginitis are related to one of three infections: bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) (aka “vaginal yeast infection”), and trichomoniasis. Bacterial vaginosis accounts for approximately 40-45% of all infections, while VVC and trichomoniasis account for about 20-25% and 15-20%, respectively. In some instances, the etiology of vaginitis may be mixed. Unfortunately, national surveillance data on vaginitis are lacking, as none are reportable diseases; however, prevalence estimates by the National Health and Nutrition Examination Survey for BV show that nearly one-third (29%) of women in the general U.S. population between the ages of 14-49 years of age are positive for this infection.
Although a number of FDA-approved therapies are available for the management of vaginitis, treatment is often challenging and further complicated by the increasing rates of treatment-resistant organisms and recurrent and persistent infections. In addition, there is a growing body of scientific evidence that identifies these infections as important risk factors for more serious health complications, particularly during pregnancy. Estimates of the direct cost of vaginitis for medical office visits and self treatment are reportedly more than $1 billion annually; however, indirect costs related to secondary complications (e.g., morbidity in pregnancy, pelvic inflammatory disease, and postoperative infections) and lost work productivity are far greater.
Accordingly, the public health implications of these infections are significant, and there is a need for improved therapeutic approaches.
Biofilm-related infections were first described in 1978 and are now believed to be a causative factor in more than 60% of human infections, particularly in their persistence and recurrence. Biofilms have been described for a wide range of chronic infections caused by bacterial and fungal organisms, including skin wounds and burns, otitis media, periodontal disease, endocarditis, urinary tract infections and device-related infections (e.g., catheters, heart valves), but are not recognized as important in the causation of vaginal infections and, thus, have not been addressed in practice by those skilled in the art of treating vaginitis.
Biofilms are highly organized populations of microorganisms embedded in a protective exopolysaccharide (i.e., carbohydrate) matrix that adhere to inert and living membrane surfaces (i.e., sessile populations) by way of adhesion proteins. In contrast to their free-floating or “planktonic” counterparts, biofilm-associated microorganisms are notoriously resistant to antimicrobial therapy—up to 1000-fold or greater—and are a source of many recurrent and recalcitrant infections. It is believed that their persistence is related, in part, to the up regulation of genes that confer a highly distinct and resistant biofilm phenotype that perpetuates growth and survival of the biofilm community. This includes the formation of biofilm matrix material, which restricts antimicrobial penetration and interferes with normal host defense mechanisms, and the generation of “persister” organisms that are essentially intolerant to killing.
The ability of biofilms to migrate over solid surfaces away from areas of high stress—a capability known as swarming—and their slow rate of growth are also believed to contribute to their pathogenicity and persistence. Evidence further suggests that established biofilms play a role in the persistence of other secondary pathogens, such as viruses, by acting as protective reservoirs that shield these organisms from destruction by the immune system and conventional antimicrobial therapies.
Boric acid or boracic acid [B(OH)3] is a weak inorganic acid with weak antimicrobial properties. In vitro, boric acid is weakly fungistatic against clinical isolates of C. albicans as well as non-albicans species, including C. tropicalis, C. glabrata and C. parapsilosis (Shubair, 1990; Prutting 1998). While boric acid also displays bacteriostatic activity in vitro against a range of common bacterial pathogens, including staphylococci and streptococci, P. aeruginosa, E. coli, and Proteus, Klebsiella and Enterobacter species (Meers 1990), the antibacterial effects of boric acid are slow acting and, in contrast to many antibiotics, appear to be independent of cell growth as dividing and stationary-phase cells have been shown to be equally affected (Meers 1990). The weak antimicrobial properties of boric acid render it surprising that boric acid would be effective in the treatment of vaginal infections, particularly those that are resistant, persistent and recurrent in nature.
Boric acid also displays other biological effects. For example, boric acid has been shown to play a role in the modulation of calcium and to stimulate wound healing through action on extracellular matrix formation and synthesis of growth factors (Dzondo 2002). Boric acid has also been shown to have anti-proliferative effects in prostate cancer cell lines and cytoprotective effects in animal models of gastric injury (Barranco 2006); (Alsaif 2004). There is also evidence to further suggest that boric acid has antiviral activity, specifically against herpes simplex virus (Skinner 1979; Rodu 1988). On a molecular level, boric acid binds cis-diol compounds, including membrane polysaccharides and carbohydrate moieties of nucleic acids involved in cell metabolism and signaling (e.g., RNA, NAD, ATP), which may explain in part the reported effects of boric acid on membrane and cellular functioning (Kim 2006); whereas the combination of boric acid and ethylene-diamine-tetra-acetic acid (EDTA) has demonstrated a unique synergy on corneal membrane permeability in vitro (Kikuchi 2005).